Apurinic/apyrimidic endonuclease (Ape1), also known as redox effector factor (Ref-1) (hereinafter Ape1/Ref-1 or Ape1) is an enzyme with a dual role. In addition to its DNA base excision repair (BER) activity, Ape1/Ref-1 also functions as a redox effector maintaining transcription factors in an active reduced state. All X-ray structures currently available for Ape1 depict the base excision repair (BER) site, and little structural information is known about the redox site. Cysteine 65 is the critical residue for redox function, unfortunately it is not solvent accessible in any structure.
Ape1/Ref-1 has been shown to stimulate the DNA binding activity of several transcription factors such as HIF-1α, NFκβ, AP-1 and p53, and others known and unknown, which are related to tumor survival and progression (Evans et al., Mutat Res 2000, 461, 83). Ape1/Ref-1 expression has been shown to be altered in a variety of cancers including breast, cervical, germ cell tumors, adult and pediatric gliomas, osteosarcomas, rhabdomyosarcomas, non-small cell lung cancer, and multiple myeloma (Puglisi et al., Oncol Rep 2002, 9, 11; Thomson et al., Am J Pediatr Hematol Oncol 2001, 23, 234; Roberston et al., Cancer Res 2001, 61, 2220; Puglisi et al., Anticancer Res 2001, 21, 4041; Koukourakis et al., Int J Radiat Oncol Biol Phys 2001, 50, 27; Kakolyris et al., Br J Cancer 1998, 77, 1169; Bobola et al., Clin Cancer Res 2001, 7, 3510). High Ape1/Ref-1 expression has also been associated with a poor outcome for chemoradiotherapy, poor complete response rate, shorter local relapse-free interval, poorer survival, and high angiogenesis (Koukourakis et al., Int J Radiat Oncol Biol Phys 2001, 50, 27; Kakolyris et al., Br J Cancer 1998, 77, 1169; Bobola et al., Clin Cancer Res 2001, 7, 3510).
Angiogenesis is an important component of cancer growth and metastasis. The formation of new blood vessels at the site of a cancerous tumor provides a source of nutrients for accelerated tumor growth and expansion as well as a path for tumor cells to enter the bloodstream and spread to other parts of the body. Thus, effective inhibition of angiogenesis is a useful mechanism to slow or prevent the growth and spread of cancer. An increase in Ape1/Ref-1 activity has been associated with angiogenesis. Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis and angiogenesis. Ape1/Ref-1 is a component of the hypoxia-inducible transcriptional complex formed on the vascular endothelial growth factor (VEGF) gene's hypoxic response element (Ziel et al., Faseb J 2004, 18, 986).
In addition to cancer, altered angiogenesis contributes to pathological conditions related to, among others, cardiovascular disease, chronic inflammatory disease, rheumatoid arthritis, diabetic retinopathy, degenerative maculopathy, retrolental fibroplasias, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, psoriasis, keloids, and systemic sclerosis.
Inhibition of angiogenesis is a desirable clinical outcome for the amelioration or prevention of diseases involving altered angiogenesis.
Given the role the redox site looks to play in pathologies, it is desirable to design and synthesize compounds which preferably selectively inhibit the redox pathway.